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Product Details of 7-keto Lithocholic Acid

CAS No. :4651-67-6
Formula : C24H38O4
M.W : 390.55
SMILES Code : C[C@H](CCC(O)=O)[C@H]1CC[C@@]2([H])[C@]3([H])C(C[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)=O
MDL No. :MFCD00271393
InChI Key :DXOCDBGWDZAYRQ-AURDAFMXSA-N
Pubchem ID :444262

Safety of 7-keto Lithocholic Acid

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H303-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of 7-keto Lithocholic Acid

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 4651-67-6 ]

[ 4651-67-6 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 67-56-1 ]
  • [ 4651-67-6 ]
  • [ 10538-59-7 ]
YieldReaction ConditionsOperation in experiment
100% With toluene-4-sulfonic acid; at 20℃; for 2h; To a solution of 7-ketolithocholic acid (5 g, 12.8 mmol), dissolved in 100 mL of dry methanol was added p-toluenesulfonic acid (1 1 g, 64.1 mmol). The solution was left to stand at room temperature for 2 h. The mixture was quenched by addition of NaHC03 saturated solution. After the evaporation of the methanol, the residue was extracted with EtOAc (3x150 mL). The combined extract was washed with brine, dried with Na2S04, and evaporated to give the methyl ester as amorphous solid (5.13 g, quantitative yield). At the solution of the methyl ester (5.13 g, 12.7 mmol) in dry pyridine (100 mL), an excess of acetic anhydride (8.4 mL, 89 mmol) was added. When the reaction was complete, the pyridine was concentrated under vacuum. The residue was poured into cold water (100 mL) and extracted with AcOEt (3x150 mL). The combined organic phases were dried (Na2S04) and concentrated to give a residue that was further purified by flash chromatography on silica gel using hexane/ethyl acetate 8:2 and 0.5% of triethylamine as eluent (4.8 g of 10 as a white solid, 84% yield over two steps). To a solution of diisopropylamine (23 mL, 0.16 mol) in dry THF (50 mL) was added dropwise a solution of n-butyllithium (60 mL, 2.5 M in hexane, 0.15 mol) at -78 C. After 30 min, trimethylchlorosilane (27.1 mL, 0.21 mol) was added. After additional 30 min, a solution of compound 10 (4.8 g, 10.7 mmol) in dry THF (70 mL) was added. The reaction was stirred at -78 C for an additional 45 min and then triethylamine (54 mL, 0.38 mol) was added. After 1 h, the reaction mixture was allowed to warm to -20 C, treated with aqueous saturated solution of NaHC03 (100 mL) and brought up to room temperature in 2 h. The aqueous phase was extracted with ethyl acetate (3x50 mL). The combined organic phases were washed then with saturated solution of NaHC03, water and brine. After drying over anhydrous Na2S04, the residue was evaporated under vacuum to give 6 g of yellow residue, that was diluted in dry CH2CI2 (50 mL) and cooled at -78 C. At this stirred solution acetaldehyde (3 mL, 53 mmol) and BF3"OEt2 (13.5 mL, 0.107 mol) were added dropwise. The reaction mixture was stirred for 2 h at -60 C and allowed to warm to room temperature. The mixture was quenched with saturated aqueous solution of NaHC03 and extracted with CH2CI2. The combined organic phases were washed with brine, dried over anhydrous Na2S04 and concentrated under vacuum. Purification by silica gel (hexane-ethyl acetate 9:1 and 0.5% TEA) gave compound 11 (4.1 g, 80%). NMR analysis demonstrated a diasteromeric ratio E/Z >95%. The E configuration at the exociclic double bond was established by dipolar coupling H3- 26 (delta 1 .67)/H-5 (delta 2.62) in Noesy spectrum (400 MHz, mixing time 400 ms). (ir)-3a-acetoxy-6-ethyliclene-7-keto-5 -cholan-24-oate (11): C29H440s The 1H NMR was recorded on Varian Inova 400 MHz, using CDCI3 as solvent: delta 6.16 (1 H, q, J = 7.0 Hz, H-25), 4.74 (1 H, m, H-3), 3.64 (3H, s, COOCHs), 2.62 (1 H, dd, J= 13.0, 3.6 Hz, H-5), 1 .98 (3H, s, COCHs), 1 .67 (3H, d, J= 7.0 Hz, H3-26), 1 .00 (3H, s, Hs-19), 0.92 (3H, d, J = 6.0 Hz, H3-21 ), 0.67 (3H, s, Hs-18). The 13C NMR was recorded on Varian Inova 100 MHz, using CDC as solvent: delta 204.5, 174.6, 170.7, 143.1 , 130.2, 72.5, 54.5, 51 .4, 50.7, 48.6, 45.2, 43.5, 39.1 , 38.9, 35.1 , 34.9, 34.1 , 33.4, 31 .0, 30.9, 28.4, 25.9 (2C), 22.8, 21 .4, 21 .2, 18.4, 12.7, 12.2.
98% With hydrogenchloride; In water; for 4h;Reflux; To a three-necked flask was added 3alpha-hydroxy-7-carbonyl-cholanic acid (32.7 g, 83.7 mmol), 120 mL of anhydrous methanol, 2 mL of hydrochloric acid (containing 22.52mmol hydrochloric acid), after the addition of reflux reaction 4.0h after TLC detection of the reaction was complete. Then the methanol was removed under reduced pressure, and the residue was dissolved in 200 mL of dichloromethane. The organic phase was washed with 100 mL of saturated sodium bicarbonate solution, 100 mL of water and 100 mL of saturated brine respectively, dried over anhydrous sodium sulfate and filtered. The mixture was evaporated under reduced pressure to give 33.2 g of a white powder (I), yield: 98%. The product was directly transferred into the next reaction without purification.
96.8% With sulfuric acid; at 62 - 64℃; for 3h; Reaction 1 : Esterification of C-24 carboxylic acid of 7-keto lithocholic acid ( LCA) 3a-hydroxy-7-keto-5P-cholan-24-oic acid (KLCA; 500.0 g, 1.28 mol) was esterified using methyl alcohol (2500 mL), in the presence of acidic catalysis (sulfuric acid, 1.0 mL) and was heated up to 62 C to 64 C for approximately 3 hours, to yield 3a- hydroxy-7-keto-5p-cholan-24-oic acid methyl ester (1 ). In this reaction, the methyl alcohol acts as the methylating reagent as well as the reaction solvent. For the work-up, the pH-value was adjusted with sodium hydroxide solution (2N) to pH 7.0 to 7.5. The solution was treated with activated carbon (25 g) for approximately 30 minutes and filtered to remove the carbon solids. Alternatively, the solution was not treated with activated carbon. To precipitate the product, water (625 mL) at 10 C to 15 C was added over 15 minutes and seeding material was added. The reaction mixture is stirred for 1 hour at 10 C to 15 C. Another portion of water ( 1 875 mL) was added over about 20 to 25 minutes. The product suspension was stirred for 30 minutes at 10 C to 15 C. The product was isolated with a centrifuge and washed with a mixture of methanol and water (1 : 1 , 350 mL). The water content of the wet material was quantified by Karl Fischer (KF). The material was dried in a tumble dryer under vacuum at NMT 70 C. The material can also be used in the next step without drying. The yield (calculated on dried product) is 501.4 g (1.24 mol, 96.8%).
96% With sulfuric acid; at 60℃; 500 g of 3alpha-hydroxy-7-keto-5beta-cholanic acid(I) was weighed into a 5000 mL three-necked flask, Then, 2500 mL of methanol and 1 mL of sulfuric acid with 98% mass fraction were added, stirred, At this time the reaction solution was white emulsion; The reaction solution was heated to 60 C for 3 hours to 8 hours, and the reaction solution was transparent and clear when TLC was used. Raw material reaction is complete; The reaction system was adjusted to pH 7.0 to 7.5 using 2 mol / L sodium hydroxide solution. System cooling to 10 ~ 15 C, the system slowly adding 625mL of water and seed, Stirring vigorously lh; then add 1875ml of water to the system, the system precipitated a large number of solid, System to keep 1 0 ~ 15 C stirring 0.5h; The above system of liquid pumping filter, filter cake with methanol and water mixed solution (volume ratio of 1: 1,350mL) Rinse; The rinsed filter cake was dried in vacuum at 50 C for 24 h, To obtain 3alpha-hydroxy-7-keto-5beta-cholanic acid methyl ester (II). The crude crude product was recrystallized using ethyl acetate / n-hexane (500 ml and 1000 ml volumes). And finally dried to give 500 g of the intermediate product of methyl 3alpha-hydroxy-7-keto-5beta-cholinate (II) The yield was 96% and the purity was 99%.
93.1% With toluene-4-sulfonic acid; for 1h;Reflux; 3alpha-Hydroxy-7-oxo-5beta-cholanoic acid (39.0 g, 100 mmol),P-toluenesulfonic acid (1.72g, 10mmol)Dissolved in methanol 120ml,Warm to reflux and keep warm for 1 hour.Cool down to room temperatureUnder stirring, 240 ml of water was slowly added to dilute and a solid precipitated.After dropping,Cool to 5C and stir for 1 hour. Filter.Solids were washed with methanol:water (1:10) solution and dried3alpha-Hydroxy-7-oxo-5beta-cholanoic acid methyl ester (37.6 g, yield 93.1%).
91.3% With thionyl chloride; at 10 - 65℃; for 3h; Add to the three bottles in turn3alpha-hydroxy-7-keto-5beta-cholic acid (III) (50 g)Methanol (360 mL) was dissolved with stirring.Cooled to below 10 c,A solution of thionyl chloride (14 mL)Then heated to 65 C,Reflux reaction 3h.The reaction ends,Cooled to 5 C,To this was added H2O (360 ml)Natural cooling crystallization,Add seed,Accelerate stirring.There is a lot of solid precipitation,Stir for 3 hours,Filter products,Dried to give IVa (47. 3 g, yield 91. 3%),Purity 98. 95%.
85.2% With methanesulfonic acid; at 30 - 60℃; for 1h;Large scale; 17.0 kg of 3alpha-hydroxy-7-keto-5beta-cholanic acid, 68 kg of methanol and 0.17 kg of methansulphonic acid were charged into a reactor. The reaction mixture was then heated to 30-60 C. for 1 hour and 25.5 kg of demineralised water was added. The mixture obtained was then stirred, cooled to 20-25 C. until a good precipitation was obtained, then cooled further to 0-15 C. The precipitate was filtered and washed with a mixture of water and methanol and further dried in an oven at about 40 C. 15 kg of methyl 3alpha-hydroxy-7-keto-5beta-cholanate (III) was thus obtained. The stoichiometric yield was 85.2%.
85.2% With methanesulfonic acid; at 30 - 60℃; for 1h;Large scale; Preparation of methyl 3a-hydroxy-7-keto-5 -cholanate. 17.0 kg of 3a-hydroxy-7-keto-5 -cholanic acid, 68 kg of methanol and 0.17 kg of methansulphonic acid were charged into a reactor. The reaction mixture was then heated to 30- 60 C for 1 hour and 25.5 kg of demineralised water was added. The mixture obtained was then stirred, cooled to 20-25 C until a good precipitation was obtained, then cooled further to 0-15 C. The precipitate was filtered and washed with a mixture of water and methanol and further dried in an oven at about 40 C. 15 kg of methyl 3a-hydroxy-7-keto-5 -cholanate was thus obtained. The stoichiometric yield was 85.2%.
81% With toluene-4-sulfonic acid; at 20℃; for 12h; 3-alpha-7-oxo CDCA (0.800 g, 2.05 mmol) was dissolved in MeOH (20 mL) and pTsOH (0.051 g, 0.266 mmol) was added. The reaction mixture stirred at room temperature for 12 hours and the solvent was removed under reduced pressure. The crude material was purified by flash column chromatography on silica gel (0-40% EtOAc in DCM, 26 minutes) to obtain KLS-2-016 (0.671 g, 81 % yield) as a white foam. 1HNMR (400 MHz, CDC13) 3.67 (s, 3H), 3.61 (dq, J = 10.7, 5.1 Hz, 1H),2.86 (dd, J = 12.5, 6.0 Hz, 1H), 2.37 (qd, J = 10.7, 9.9, 6.2 Hz, 2H), 2.29 -2.15 (m,2H), 2.08 - 1.05 (m, 24H), 1.02- 0.83 (m, 4H), 0.66 (s, 3H).?3C NMR (100 MHz, CDC13) 212.1, 174.9, 71.2, 55.0, 51.7, 49.7, 49.1, 46.3, 45.6, 42.9, 42.9, 39.2, 37.6, 35.4, 35.4, 34.4, 31.3, 31.2, 30.1, 28.5, 25.0, 23.3,21.9, 18.6, 12.3.
79% With toluene-4-sulfonic acid; at 80℃; for 4h; To a solution of Reference Example 1A (246.0 g, 629.9 mmol) in methanol (2 L), p-toluenesulfonic acid (10.9 g, 63.0 mmol) was added in one portion, and they were reacted at 80C for 4 hours. After being cooled to room temperature, they were evaporated to dryness, and quenched with saturated sodium bicarbonate solution (1500 mL). Then, the aqueous layer was extracted with ethyl acetate (1500 mL x 3). The combined organic layer was washed with brine (1000 mL x 3), dried over sodium sulfate, filtered and evaporated to dryness. The residue was recrystallized (ethyl acetate, 500 mL) to give Reference Example 1 B (white solid, 202 g, 79% yield). 1H NMR (400 MHz, CHLOROFORM-d) delta 3.66 (s, 3H), 3.55-3.62 (m, 1H), 2.85 (dd, J=6.02, 12.55 Hz, 1H), 2.28-2.43 (m, 2H), 2.13-2.26 (m, 2H), 1.64-2.04 (m, 10H), 1.19-1.51 (m, 11H), 1.00-1.17 (m, 3H), 0.86-0.97 (m, 3H), 0.65 (s, 3H).
77% With sulfuric acid;Reflux; Toasolutionofcompound1.1(20g,51.2mmol)inmethanol(100mL)wasaddedconcentratedH2SO4(1g).TheresultedmixturewasstirredatrefluxforovernightuntilthestartingmaterialwasdisappearedunderthemonitorofTLC.Thesolventwasevaporatedundervacuum,theresiduewaspartitionedbetweenwater(100mL)andethylacetate(100mL),and theorganiclayerwasseparatedandwashedwithasaturatedsolutionofaqueousNaHCO3andbrine,driedoveranhydrousNa2SO4,filteredandconcentrated.TheresiduewaspurifiedbyFlashchromatography (DCM/MeOH95:5)toaffordcompound1.2 (16g,yield:77)asalightyellowoil.m/z:[M+H]+405
77% With sulfuric acid;Reflux; Compound 1.1 (20 g, 51.2 mmol) was dissolved in methanol (100 mL)Concentrated sulfuric acid (1 g) was added and the reaction was heated under reflux overnight.TLC tracking the disappearance of raw materials,The solvent was distilled off under reduced pressure, water (100 mL) and ethyl acetate (200 mL) were addedThe phases were separated and washed with saturated sodium bicarbonate and saturated brine, respectively, and dried over anhydrous sodium sulfate. The crude product was purified by flash column chromatography (dichloromethane / methanol = 95: 5) to give compound 1.2 (16 g, yield: 77%) as a pale yellow oil
With sulfuric acid;Reflux; A solution of KLCA in methanol is contacted with conc. H2S04 and heated to reflux. The solution is cooled and diluted with water to initiate crystallization. The solids are filtered and washed with a mixture of methanol and water to afford Compound 10a.
With acetyl chloride; at 20℃; for 19.5h; Compound (1-1) was prepared by following the literature method (J. Med. Chem., 2012, 55, 8493). To a solution of compound (1-1) (30 g, 76.9 mmol) in MeOH (450 mL) was added acetyl chloride (2.3 g, 2.1 mL, 29.5 mmol) at rt and the reaction was stirred at rt for 19.5 h. Concentrated, chased with anhydrous THF and dried in vacuo to give compound (1-2) (32.1 g, 103% yield) as a white solid.
With sulfuric acid; at 25 - 35℃; for 24h;Inert atmosphere; To a mixture of 3a-hydroxy-7-keto-5P-cholanic acid (I) (80 g) and methanol (400 mL), concentrated sulphuric acid (1.6 mL) was added slowly under nitrogen atmosphere at 25-35 C. The reaction mass was stirred for 24 hours at 25-35 C. Triethylamine (9.6 mL) was added to the reaction mass and the reaction mass was stirred for 10-20 minutes. The aqueous solution of sodium bicarbonate (4%, 800 mL), was added to the reaction mass drop wise over a period of 3 hours and continued stirring for one hour and then filtered and washed with water. The wet solid was mixed with ethyl acetate (120 mL) and heated to 45 C. The reaction mass was stirred for 10-20 minutes at 40-50 C and cooled to 25-35 C. Brine (40 mL) was added to the reaction mass and the reaction mass was stirred for 10-20 minutes at 27C. The organic layer was separated and hexane (1200 mL) was added to it slowly over a period of 3 hours. The reaction mass was stirred for 1 hour at 27 C and filtered. The solid was washed with 5% ethyl acetate in hexanes mixture (160 mL). The solid was dried under vacuum at about 45 C for 8-10 hours to afford the desired compound. Yield: 67.25 g. Purity (by HPLC): 81.15%
With sulfuric acid; General procedure: Reference to the preparation method reported in the above-mentioned document WO2013192097: 3alpha-hydroxy-7-ketocarbonyl-5beta-cholesta-24-acid (KICA) as a starting material, under the catalytic conditions of methanol, sulfuric acid, the esterification reaction occurs A Esters methyl esterification intermediate 1;Li[N(CH(CH3)2)2] reacts with trimethylchlorosilane at -10 to -30C to protect the 3 hydroxyl groups with silane.Intermediate 3 obtained.Intermediate 3 at -50 ~ -70 degrees, plus acetaldehyde reaction to obtain vinyl intermediate 4,This Intermediate 4 solution was used directly in the next step.Intermediate 4 was hydrolyzed under 30% sodium hydroxide and neutralized to give Intermediate 5.Total yield 47,5% (calculated from KLCA).Intermediate 5 was catalytically hydrogenated under 5% palladium on carbon to afford Intermediate 6, yield 81.2%.The intermediate 6 was reduced with sodium borohydride at 85-110 degrees to obtain crude bebechoic acid with a yield of 77.9 %.
43 g With sulfuric acid; at 25 - 55℃; for 3h; Concentrated sulfuric acid (1.0 ml) was slowly added to a mixture of methanol (250 ml) and 3cL-hydroxy-7-keto-5f3-cholanic acid (50 gms) at 25-30C. Heated the reaction mixture to 50-55C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30C. Aqueous sodium bicarbonate solution was slowly added to the reaction mixture at 25-30C and stirred for 60 minutes at the same temperature. Filtered the solid and washed with water. Ethyl acetate (75 ml) was added to the obtained wet compound at 25- 30C. Heated the reaction mixture to 45-50C and stirred for 50 minutes at the same temperature. Reaction mixture was washed with aqueous sodium chloride solution. Both the aqueous and organic layers were separated. N-heptane was slowly added to the obtained organic layer within 2 hours at 25-30C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed with a mixture of ethyl acetate, heptane and dried to get the title compound. Yield: 43.0 gms; Reported M.R: 62-64C.

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  • 2
  • [ 4651-67-6 ]
  • [ 10538-59-7 ]
YieldReaction ConditionsOperation in experiment
95% With toluene-4-sulfonic acid; In methanol;Reflux; (2) 830 g of intermediate 1Added to 10L of methanol,Add 15 grams of p-toluenesulfonic acid,Heat reflux, TLC control tracking,After the reaction was completed, it was cooled to room temperature, and the pH was adjusted to approximately 7 with saturated sodium bicarbonate. The solvent was distilled off under reduced pressure and filtered to obtain 816 g of Intermediate 2 in a yield of 95%.
25.3 g With sulfuric acid; In methanol; for 4h;Reflux; Add 125ml of methanol and 25g of KLCA to the reaction flask at room temperature, add 0.25ml of concentrated sulfuric acid while stirring, and reflux for 4h under the condition of temperature rising. The reaction is completed. About 100ml of water was added dropwise to the system, stirring was continued, and a large amount of solid powder was gradually formed. After filtration and cake washing, the mixture was air-dried at 50 C for 15h to obtain 25.3g of white solid product in a yield of 97.7%.
  • 3
  • [ 75-75-2 ]
  • [ 4651-67-6 ]
  • [ 10538-59-7 ]
YieldReaction ConditionsOperation in experiment
In methanol; for 2h;Reflux; AB - 2 - AB - 3 preparation process is as follows: which comprises the AB - 2 (76.2g), methanesulfonic acid (400 mg) of methanol solution (380 ml) stirring and heating to reflux. Stirring 2 hours, HPLC monitoring after the reaction is finished (raw material _AOMARKENCODELTX0AO _ 1%), reduced pressure to remove the methanol (50 C). The reaction liquid temperature to the room temperature, adding dichloromethane (600 ml) and a saturated aqueous solution of sodium bicarbonate (250 ml), water (180 ml), stirring 30 minutes, layered (there may be emulsified phenomenon, filtering it will obviously good layered), then the aqueous layer 150 ml dichloromethane extraction, merge all organic layer, saturated NaCl solution (300 ml) washing, for anhydrous magnesium sulfate (38g) drying 2 hours (after drying the water content is 0.07%). Filtering, the filtrate without purification directly used for AB - 4 preparation.
  • 4
  • [ 10538-59-7 ]
  • [ 4651-67-6 ]
YieldReaction ConditionsOperation in experiment
95% With sodium hydroxide; In tetrahydrofuran; methanol; for 3h;Reflux; The compound of formula (11) (5.7 g, 15.78 mmol) was dissolved in methanol (48 mL) andTetrahydrofuran (12 mL) was added sodium hydroxide (2.5 g, 63.12 mmol) and refluxed for 3 h. TLC detection reaction finishedAfter the addition of dilute hydrochloric acid, adjust the pH to 5, remove the solvent under reduced pressure, add water (80mL), extract with dichloromethane (30mL × 3), mergeThe organic phase was washed with water, washed with saturated brine, dried over anhydrous Na2SO4, concentrated and purified by silica gel column chromatography (DCM: MeOH = 20: 1)The compound of formula (9) (7-keto-cholic acid) (4.73 g of a white solid in 95% yield).
74% With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 4h; To a solution of methyl-3alpha-hydroxy-7-oxo-5beta-cholanoate (Compound 3; 269 mg, 0.66 mmol) in THF was added LiOH (12 mL, 0.3M aqueous soln) and the mixture was stirred at room temperature for 4 hours. The mixture was acidified with 1M HCl until pH 1 and the product extracted with EtOAc (3*30 mL). The organics were combined, dried over anhydrous sodium sulfate, filtered and concentrated in the rotatory evaporator to yield a crystalline solid (192 mg, 0.49 mmol, 74%). MS (ESI+): m/z 413.2 [M+Na]+. 1H NMR (300 MHz, MeOD) delta 3.60-3.46 (m, 1H), 2.99 (m, 1H), 2.54 (t, J=11.2 Hz, 1H), 2.34 (m, 1H), 2.26-2.10 (m, 2H), 2.09-1.71 (m, 7H), 1.71-1.25 (m, 9H), 1.25-0.99 (m, 8H), 0.96 (d, J=6.5 Hz, 3H), 0.71 (s, 3H).
32 g With water; sodium hydroxide; In methanol; for 2h;Reflux; Dissolve 40 g of intermediate 6 in 100 g of ethanol, add 5 g of water and 10 g of sodium hydroxide, and stir at reflux for 2 hours. The reaction is monitored by TLC. The pH is adjusted to less than 2 with dilute hydrochloric acid, and a large amount of solids are precipitated. The product 7-ketolithocholic acid 32g, the purity by HPLC was greater than 99.5%
  • 5
  • [ 67-56-1 ]
  • [ 4651-67-6 ]
  • [ 10538-59-7 ]
YieldReaction ConditionsOperation in experiment
91% With sulfuric acid; at 60℃; for 12h;Reflux; takes obtained white solid in 150 ml single port in round bottomed flask, add 60 ml methanol, heating to 60 C, dropwise 1 ml 98% concentrated sulfuric acid, reflux stirring reaction 12h, detecting the completion of the reaction by TLC, adding 2g sodium bicarbonate, to be bubble-free after the formation, filtering to remove the excessive sodium bicarbonate, the filtrate and steaming and remove most of the methanol, the remaining liquid of ethyl acetate extraction, evaporation of the ethyl acetate, to obtain white solid 1.66g compound (III) is, yield 91%.
 

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